Synthesis of naphthalene derivatives

ABSTRACT

2-(6-METHOXY-2&#39;&#39;-NAPHTHYL)PROPANAL IS SYNTHESIZED FROM 6-METHOXY-2-ACETYLNAPHTHALENE BY TREATMENT WITH A PHOSPHONIUM YLID, SULFCNIUM YLID OR A PHOSPHONATE CARBANION FOLLOWED BY ACID HYDROLYSIS TO THE ALDEHYDE WHICH IS CONVERTED INTO 2-(6&#39;&#39;-METHOXY-2&#39;&#39;-NAPHTHYL)PROPANOL BY REDUCTION AND INTO 2-(6&#39;&#39;-METHOXY-2&#39;&#39;-NAPHTHYL)PROPIONIC ACID BY OXIDATION, THESE COMPOUNDS HAVE ANTI-INFLAMMATORY ACTIVITY.

United States Patent Office 3562336 Patented Feb. 9, 1971 vary fromabout --80 C. to the reflux temperature of 3,562,336 the reactionmixture. The reaction temperature is not SYNTHESIS OF NAPHTH NDERIVATIVES critical and generally it is preferable to operate at fromPeter H. Nelson, Los Altos, Calif., assignor to Syntex about 0 C to roomtem perature. For optimum results, Colporahmi i Panama a comm-anon ofPanama it is important that the reaction be conducted under as NoDrawing. Filed July 24, 1968, Ser. No. 747,071 5 Int CL C07c 43/20 nearanhydrous conditions as possible and under inert Us, Cl, 260-613 4Claims oxygen-free atmosphere such as nitrogen, argon, and the like.

The intermediate (II), upon treatment with an inor- ABSTRACT OF THEDISCLOSURE 10 ganic or organic acid, yields the aldehyde (III). Thisreaction is preferably carried out using a strong mineral acid, such assulfuric acid, in an aqueous organic solvent, such as dioxane, diglyme,tetrahydrofuran, and the like, at an elevated temperature, such asreflux temperature of the reaction mixture. Other acids which can beused are perchloric acid, methanesulphonic acid, p-toluenesulfonic acid,hydrochloric acid. The temperature is not critical but it is preferredto operate at room temperature or above to complete the reaction withina reasonable time. The concentration of acid is not critical butgenerally there is used 0.3% to 2% v./v.

Phosphonium ylids of Formula A which can also be illustrated as follows:

2-(6-methoxy-2-naphthyl)propanal is synthesized from6-methoxy-2-acetylnaphthalene by treatment with a phosphonium ylid,sulfonium ylid or a phosphonate carbanion followed by acid hydrolysis tothe aldehyde which is converted into 2-(6'-methoxy-2'-naphthyl)propanolby reduction and into 2-(6'-methoxy-2'-naphthyl)propionic acid byoxidation, these compounds have anti-inflammatory activity.

This invention relates to the novel synthesis of naphthalenederivatives. More particularly, the present invention relates to thesynthesis of 2-(6'-methoxy-2'-naphthyl)propanal, 2(6-methoxy-2-naphthyl)propan-l-ol (9 )a and2-(6'-methoxy-2'-naphthyl)propionic acid and novel (A intermediates. inwhich R is as defined above, can be prepared by the The process of thepresent invention can be outlined as reaction of a triphenylphosphoniumhalide, e.g. the brofollows wherein R represents lower alkyl, phenyl orsubmide or chloride, with a reagent capable of removing stituted phenyl.hydrogen halide, such as alkyl and aryl lithium, alkali (H) (JHOR C CH3C-CH3 l CHsO J (EH CH3 CH: 0 (EH: o-onzoH C'3 J-H 0-00211 \J \2 I i H HH CH30 CH:O CH30 In the practice of the above process, 6-methoxy-2-metal amides, and the like. Triphenylphosphonium halidesacetylnaphthalene (I) is reacted with a phosphonium ylid can be preparedby known methods, such as by reacting of the following formula in whichR is as defined above: triphenylphosphine with the appropriate organichalide.

Suitable procedures for preparing the phosphonium ylid ()3P:CHOR aredescribed by A. W. Johnson, Ylid Chemistry,

(A) Academic Press Inc., New York (1966) and in US.

Patents 3,078,256 and 3,130,219.

Yield the y- Y Phfinoxy The aldehyde (III), upon treatment with anoxidizing phefnoxypropenyl)111aphtha1ene Thls reac' agent, such aschromium trioxide in an organic solvent tion is carried out using aboutequimolar amounts of the inert to the reaction or chromic acid yieldsthe acid phosphonium ylid and 6-methoxy-2-acetylnaphthalene. 0 (IV)Suitable organic solvents for the reaction medium include 6Alternatively, the aldehyde n is Subjected to hydrocarbons, Suchbenzene: toluene hexane, and the duction as by treatment with sodiumborohydride, lithium like; ethers, such as diethyl ether,tetrahydrofuran, dioxaluminum hydride or diborane to yield the alcohol(\7) ane, monoglyme, dlglymc, and the llke; and "fixtures Compounds ofFormula II above can also be prepared thereof. Any organic solvent canbe used for the reaction medium so long as it is inert to the reaction.When the phosphonium ylid (A) is prepared in situ, the ketone (I) can beintroduced as a solution using the same solvent or '2 a solventdifferent but miscible with that used for the or a carbanion of theformula: preparation of the ylid. The reaction generally goes to 70 0completion in from about 0.5 hour to about 48 hours depending upon suchfactors as the temperature and reactiv- WWW-C1103 ity of the ylid andaldehyde. The reaction temperature can in which R and R" representslower alkyl or phenyl and by reacting 6-methoxy-2-acetylnaphthalene witha sulfoniurn ylid of the type:

R is as defined above. Sulfonium ylids are prepared by the reaction of adialkyl sulfide with a halomethyl ether (x-CH OR; x is chloro or bromoand R is as defined above) to give [R S+CH OR]x which is converted intothe ylid by reaction with a strong base such as phenyl lithium, butyllithium, and the like. The carbanion is produced by the action of sodiumor potassium on the corresponding phosphonate which is obtained byreaction of trialkoxyphosphine with a halomethyl ether (x-CH OR) See A.W. Johnson, Ylid Chemistry, Academic Press Inc., New York, page 203 etseq. (1966).

The compounds of Formulas II, IV and V are therapeutically usefulanti-inflammatory agents, analgesic agents and anti-pyretic agents.Thus, they are useful for the treatment of inflammatory conditions ofthe skin, bones and muscles and pain associated therewith, such ascontact dermatitis, bursitus, arthritis, pruritus, and the like. Theycan be administered and used in the same way as phenylbutazone. Forexample, they can be administered orally to animals such as cats, dogs,horses, and the like, for the treatment of painful arthritic andskeletal muscular disorders.

The term lower alkyl, as used herein, refers to saturated aliphatichydrocarbons, branched or straight chain, of one to 8 carbon atoms suchas methyl, ethyl, propyl, isopropyl, and the like. The term substitutedphenyl, as used herein, refers to a substituted phenyl such as loweralkylphenyl, halophenyl, nitrophenyl, lower alkoxyphenyl, and the like.

The following examples are provided to illustrate the present invention.

EXAMPLE 1 (A) A mixture of g. of triphenylphosphine, 1.5 molarequivalents of methoxymethyl chloride and 200 ml. of ether is refluxedfor about two hours. The reaction mixture is cooled and the precipitatedmethoxymethyltriphenylphosphonium chloride collected by filtration.

(B) Two grams of the rnethoxymethyltriphenylphosphonium chloride of PartA is stirred under nitrogen and an ethereal solution of 1.1 molarequivalents of phenyl lithium is added at about 0 C. One molarequivalent of 6-rnethoxy-2-acetylnaphthalene in benzene is added quicklywhile maintaining the temperature at about 0 C. The reaction mixture isallowed. to come to room temperature and methanol is added until asubstantially clear solution is obtained. The solution is then Washedwith water, dried over magnesium sulfate and evaporated to dryness. Theresidue is dissolved in hot ethyl acetate, an equal volume of hot hexaneadded, cooled, filtered to remove tirphenylphosphine oxide, and thefiltrate evaporated. This residue is dissolved in hot ethyl acetate, anequal volume of hot hexane added, cooled, filtered and the filtrateevaporated to yield 2-[2'-(1-methoxypropenyl)]-6-methoxynaphthalene (II;R is methyl).

(C) Three grams of 2-[2'-(1-methoxypropenyl)]-6- methoxynaphthalene isdissolved in 60 ml. of dioxane and ml. of water containing 0.5 ml. ofconcentrated sulfuric acid. The solution is refluxed under nitrogen forthree hours, cooled, poured into 100 ml. Water and extracted with ether.The ether extract is washed with dilute aqueous sodium bicarbonate,dried over magnesium sulfate and evaporated to yield2-(6'-rnethoxy-2'-naphthyl) propanal (III) which is recrystallized fromethyl acetate:

hexane.

EXAMPLE 2 A solution of 2 g. of 2-(6'-methoxy2'-naphthyl)-propanal in 20ml. of anhydrous tetrahydrofuran is cooled to 75 C. in a Dry Ice-acetonebath and treated with a previously cooled solution of 0.6 g. of lithiumaluminum hydride in 20 ml. of anhydrous tetrahydrofuran. Aftermaintaining the reaction mixture at -75 C. for one hour and at roomtemperature for minutes, it is poured into ice Water and extractedseveral times with ethyl acetate. These extracts are washed with dilutehydrochloric acid and then with Water to neutrality, dried overanhydrous sodium sulfate and evaporated to dryness under vacuum. Theresidue is crystallized from acetone:hexane to yield2-(6-methoxy-2'-naphthyl) propanol.

EXAMPLE 3 To a stirred solution of l g. of 2-(6-methoxy-2'-naphthyl)propanal in 10 ml. of acetone, cooled to 0 C., is added undernitrogen the theoretical amount of a solution of 8 N chromic acid(prepared by mixing 26 g. of chromium trioxide with 23 ml. ofconcentrated sulfuric acid and diluting with water to 100 ml.). Themixture is then stirred for five minutes at 0-5 C. and diluted withwater. The solid which forms is collected by filtration, washed withwater and dried under vacuum to yield 2-(6'-methoxy-2-naphthyl)-propionic acid which may be further purified byrecrystallization from aqueous methanol.

EXAMPLE 4 (A) The procedure of Example 1A is repeated using an requivalent amount of (1) phenoxymethyl chloride, (2)pmethoxyphenoxymethyl chloride, (3) p-nitrophenoxymethyl chloride, (4)ethoxymethyl chloride and (5) npropoxymethyl chloride in place ofmethoxymethyl chloride to yield: (1) phenoxymethyltriphenylphosphoniumchloride, (2) p-methoxyphenoxymethyltriphenylphosphonium chloride, (3)p-nitrophenoxymethyltriphenylphosphonium chloride, (4)ethoxymethyltriphenylphosphonium chloride and (5)n-propoxyrnethyltriphenylphosphonium chloride, respectively.

(B) The foregoing triphenylphosphonium chlorides are reacted with phenyllithium to yield the corresponding phosphonum ylid which is reacted with6-methoxy-2-acetylnaphthalene according to the procedure of Example 1Bto yield: (1) 2-[2'-(1'-phenoxypropenyl)] 6 methoxynaphthalene (II; R isphenyl), (2) 2-[2'-(l'-p-methoxyphenoxypropenyl)] 6 -methoxynaphthalene(II; R is pmethoxyphenyl), (3) 2 [2' (1 pnitrophenoxypropenyl)1-6-methoxynaphthalene (II; R is p-nitrophenyl),(4) 2-[2-(1'-ethoxypropenyl)]-6-methoxynaphthalene (II; R is ethyl) and(5) 2-[2-(1-n-propoxypropenyl)] 6 -methoxynaphthalene, respectively,each of which can be treated with acid according to the procedure ofExample 1G to yield 2-(6'-methoxy-2-naphthyl)propanal.

Other substituted phenoxymethyl chlorides which can be used in the aboveprocedure (4A) are: 4-t-octylphenoxymethyl chloride,2-methoxyphenoxymethyl chloride, 4-bromophenoxymethyl chloride,2-chlorophenoxymethyl chloride, 3-chlorophenoxymethyl chloride,4-chlorophenoxymethyl chloride, 2,4-dichlorophenoxymethyl chloride, 4methylphenoxymethyl chloride, 2,5 dichlorophenoxymethyl chloride, 2,6dichlorophenoxymethyl chloride, 2,3,4-trichlorophenoxymethyl chloride,4-chloro-2-methylphenoxymethyl chloride, 3,5-dimethyl 4chlorophenoxymethyl chloride, 3-nitro-4-chlorophenoxymethyl chloride,and 3-methoxy-4-chlorophenoxymethyl chloride to yield the correspondingsubstituted phenoxymethyltriphenyl phosphonium chloride.

EXAMPLE 5 A solution of 1 g. of sodium borohydride in 3 ml. of water isadded to an ice-cooled solution of 2 g. of 2-(6-methoxy-2'-naphthyl)propanal in ml. of methanol and the mixture thenallowed to stand for 16 hours at room temperature. Excess reagent isdecomposed by the addition of acetic acid and the solution is thenconcentrated to small volume under vacuum and diluted with water. Theproduct is extracted with ethyl acetate and the extracts are washed withwater, dried and evaporated to yield 2-(6'-methoxy-2-naphthyl)propanol.

5 What is claimed is: 1. A compound selected from the group of compoundsrepresented by the formula:

CHOR

CHaO

3. A compound according to claim 1 wherein R is phenyl.

4. A compound according to claim 1 wherein R is methyl.

References Cited UNITED STATES PATENTS 3,130,219 4/1964 Pommer et a1.260598 OTHER REFERENCES Wagner et al.: Synthetic Organic Chemistry(1953), pp. l48l53 and 419420.

Wittig et a1.: Chemische Berichte, vol. 95 (1962), pp.

BERNARD HELFIN, Primary Examiner US. Cl. X.R. 260600, 520, 999

